Association between Thymic Function and Allogeneic Hematopoietic Stem Cell Transplantation Outcome: Results of a Pediatric Study Francesco Saglio 1 , * , Silvia Cena 2 , Massimo Berger 1 , Paola Quarello 1 , Viola Boccasavia 2 , Federica Ferrando 2 , Laura Pittana 1 , Benedetto Bruno 2 , Franca Fagioli 1 1 Pediatric Onco-Hematology, Stem Cell Transplantation, and Cellular Therapy Division, A.O.U. Citta’ della Salute e della Scienza di Torino, Ospedale Infantile Regina Margherita, Torino, Italy 2 Division of Hematology, A.O.U. Citta’ della Salute e della Scienza di Torino, Presidio Molinette, University of Torino and Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino, Italy Article history: Received 14 August 2014 Accepted 10 February 2015 Key Words: sjTREC Allogeneic hematopoietic stem cell transplantation Pediatric abstract Robust T cell function recovery has been shown to be crucial in determining allogeneic hematopoietic stem cell transplantation (HSCT) outcome, and there is growing evidence that the thymus plays a central role in regulating this process. We performed a long-term analysis of the role of thymic activity recovery in a population of pediatric patients undergoing allogeneic HSCT by signal joint T cell receptor excision circle (sjTREC) quantification. In this study, characterized by a long-term follow-up (median, 72 months), we found patients with higher levels of sjTRECs before transplantation had a statistically significant reduced risk of death compared with patients with lower values (relative risk, .31; 95% confidence interval, .30 to .32; P ¼ .02), showing this different outcome was mainly related to a reduction of relapse incidence (14% versus 43%, P ¼ .02). Unlike previous reports, we observed no correlation between sjTREC levels and lymphocyte recovery. Moreover, we confirmed that only graft-versus-host disease influenced thymic activity after transplantation. In conclusion, our results suggest an association between pretransplantation thymic activity and the long- term outcome of pediatric patients undergoing HSCT, mainly through a reduction of relapse opportunities. Ó 2015 American Society for Blood and Marrow Transplantation. INTRODUCTION Allogeneic hematopoietic stem cells transplantation (alloHSCT) is 1 of the best therapeutic options available for pediatric patients affected by various malignant diseases and other nonmalignant disorders involving the hematopoietic system [1]. T lymphocyte function recovery is a crucial event in determining the prognosis of patients undergoing alloHSCT because its prolonged impairment may be related to the occurrence of infectious complications and, in the malignant setting, also to the recurrence of primary disease [2,3]. T cell recovery after alloHSCT typically evolves throughout 2 distinct phases, called thymus-independent, or early phase, and thymus-dependent, or late phase. The thymus- independent phase consists of the peripheral expansion of mature T cells transferred to the patient with the graft [4,5]. The thymus-dependent phase consists of the generation of new naive T cells from the donor-derived hematopoietic progenitors occurring in the recipient’s thymus. The thymus- dependent phase accounts for the most durable reconstitu- tion of the T cell compartment, generates T cell receptor repertoire diversity [6], and requires a functionally active thymus [7]. Thymic function can be evaluated through the evaluation of the signal joint T cell receptor excision circles (sjTRECs) by quantitative PCR. sjTRECs are episomal DNA fragments resulting from the deletion of the T cell receptor d region during T cell receptor a locus rearrangement. Because they cannot replicate and are not duplicated, they are diluted out during cell division, allowing a direct evaluation of recent thymic output [8,9]. Previous studies explored the relationship between sjTREC levels and the kinetics of the phenotypic and func- tional changes in peripheral T cells after alloHSCT, showing a direct correlation between sjTREC levels and the percentage Financial disclosure: See Acknowledgments on page 1104. * Correspondence and reprint requests: Francesco Saglio, MD, Pediatric Onco-Hematology, Stem Cell Transplantation, and Cellular Therapy Divi- sion, A.O.U. Citta’ della Salute e della Scienza di Torino, Ospedale Infantile Regina Margherita, Piazza Polonia 94,10126 Torino, Italy. E-mail address: francesco.saglio@hotmail.it (F. Saglio). http://dx.doi.org/10.1016/j.bbmt.2015.02.010 1083-8791/Ó 2015 American Society for Blood and Marrow Transplantation. Biol Blood Marrow Transplant 21 (2015) 1099e1105 Biology of Blood and Marrow Transplantation journal homepage: www.bbmt.org